This is a broadly directed program to investigate fundamental advances in chemical synthesis of novel biologically active natural products. The major areas have been categorized by distinct structural motifs and bioactivity. I. Novel Marine Oxazoles. Research will execute a synthesis of Hennoxazole A, a promising lead in the search for new antiviral agents. While this unique bis-oxazole also displays peripheral analgesic activity comparable to indomethacin, its unusual structure and antiviral significance (IC50 0.6 m/mL), make this a compelling case for chemical synthesis. Phorboxazole A exhibits remarkable antitumor activity in all 60 NCI cell lines, and is one of the most potent cytostatic macrocycles yet discovered. Chemical studies will explore enantioselective allylstannane condensations with aldehydes as a convergent construction of carbohydrates which are C-linked to a heterocyclic core. Overall a general approach to novel nucleosides is detailed. II. Novel Anti-Infective Cyclitols. Studies for synthesis of funiculosin and related 4-hydroxy-2-pyridinones will provide novel C-linked heterocyclic cyclitols as potent antifungal agents. Funiculosin shows in vivo antifungal potency comparable to griseofulvin with low toxicity. The Saegusa oxidation will be explored as a ring closure event, and internal conjugate additions in funiculosin, as well as apiosporamide, will be examined as a relevant chemical feature of bioactivity. III. Polycyclic Marine Alkaloids. Zoanthamine is an alkaloid with anti-inflamatory and analgesic effects. Proposed studies will investigate Pd(O)-catalyzed cross-coupling reactions for ring closure. Studies of the Michael reaction will be exploited for stereocontrolled formation of quaternary carbons in ring annelation processes. IV. Large-Ring Carbocycles. Efforts to complete synthesis studies of the lankacidins are described. These macrocyclic antitumor agents exhibit important antibiotic effects against resistant organisms. New strategies for macrocyclization are introduced. Acyl nitrene insertions for preparation of lankacyclinol are described.